Glypican-3-specific antibody and uses thereof
Inventors
Assignees
University of Pennsylvania Penn • US Department of Veterans Affairs
Publication Number
US-9790267-B2
Publication Date
2017-10-17
Expiration Date
2032-10-31
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Abstract
The present invention relates to compositions and methods for diagnosing and treating diseases, disorders or conditions associated with dysregulated expression of GPC3. The invention provides novel antibodies that specifically bind to glypican-3 (GPC3). The invention also relates to a fully human chimeric antigen receptor (CAR) wherein the CAR is able to target GPC3.
Core Innovation
The present invention relates to compositions and methods for diagnosing and treating diseases, disorders or conditions associated with dysregulated expression of glypican-3 (GPC3). It provides novel antibodies that specifically bind to GPC3 and describes a fully human chimeric antigen receptor (CAR) that targets GPC3. The invention includes isolated polynucleotides and polypeptides encoding human anti-GPC3 antibodies or fragments, methods for diagnosing GPC3-associated conditions using these antibodies, and methods of inhibiting growth of GPC3-expressing tumor cells by contacting them with anti-GPC3 antibodies or fragments.
The invention further provides isolated nucleic acid sequences encoding CARs comprising a human GPC3 binding domain and a CD3 zeta signaling domain, optionally including co-stimulatory signaling domains such as CD28 or 4-1BB. The CAR's human GPC3 binding domain can be a human antibody or a fragment including Fab, F(ab′)2, Fv, or single chain Fv (scFv). The invention also encompasses methods using cells engineered to express these CARs for adoptive therapy.
The problem being solved is the need for specific targeting moieties to direct immunotherapy against hepatocellular carcinoma (HCC), a leading cause of cancer-related death. Existing tumor antigens do not offer suitable antibody-targetable extracellular domains. GPC3 is a cell surface, glycophosphatidylinositol-linked proteoglycan re-expressed in a high frequency of neoplastic hepatocytes, making it an attractive and specific target for HCC tumor immunotherapy. However, GPC3-specific T bodies, especially the single chain variable fragments (scFv) as targeting moieties, remain underdeveloped. The present invention addresses the need for human-derived GPC3-specific antibodies and CARs using these antibodies for effective immunotherapy and diagnostics related to GPC3 expression.
Claims Coverage
The patent includes two independent claims focusing on nucleic acids encoding single chain human anti-GPC3 antibody fragments and vectors comprising these nucleic acids, covering both amino acid and nucleic acid sequences.
Isolated polynucleotide encoding single chain human anti-GPC3 antibody fragment
An isolated and substantially purified polynucleotide encoding a single chain human anti-GPC3 antibody fragment, comprising a heavy chain variable region and light chain variable region, where the amino acid sequences of these variable regions are selected from specific groups consisting of SEQ ID NOs: 12 and 17, 13 and 18, 14 and 19, or 15 and 20.
Isolated polynucleotide comprising nucleic acid sequences encoding heavy and light chain variable regions
The isolated polynucleotide comprises nucleic acid sequences encoding the heavy and light chain variable regions, where the nucleic acid sequences are selected from the group consisting of SEQ ID NOs: 52 and 57, 53 and 58, 54 and 59, or 55 and 60.
Isolated vector comprising the isolated polynucleotide
An isolated and substantially purified vector comprising the isolated polynucleotide encoding the single chain human anti-GPC3 antibody fragment.
Vector is a viral vector of specific types
The vector can be a viral vector selected from adenoviral vector, adeno-associated virus vector, retroviral vector, poxvirus, herpes simplex virus I, or lentiviral vector.
The claims cover isolated nucleic acids encoding specific binding regions of human anti-GPC3 scFv antibody fragments, nucleic acid sequences encoding these variable regions, and vectors (including viral vectors) comprising these nucleic acids, thus protecting compositions and constructs central to the specific targeting of GPC3 using human antibodies.
Stated Advantages
The antibodies bind specifically to human GPC3 with high affinity, ranging approximately from 5.0 to 110.9 nM.
The CAR-modified T cells exhibit antigen-specific cytotoxicity and proinflammatory cytokine secretion against GPC3-expressing cancer cells.
Use of fully human antibodies and CAR constructs reduces immunogenicity for human therapy.
CAR-modified T cells can replicate in vivo to achieve long-term persistence leading to sustained tumor control.
Documented Applications
Diagnosis of conditions associated with GPC3 expression, including liver cancer, via detecting GPC3 in biological samples using the human anti-GPC3 antibodies.
Therapeutic treatment of cancers associated with dysregulated expression of GPC3, particularly hepatocellular carcinoma (HCC) and other cancers such as pancreatic, ovarian, stomach, lung, and endometrial cancers, using anti-GPC3 antibodies or CAR-engineered T cells.
Adoptive cellular immunotherapy employing T cells genetically engineered to express fully human anti-GPC3 chimeric antigen receptors (CARs) for targeting and killing GPC3-expressing tumor cells.
Ex vivo immunization of T cells with CAR constructs for administration to patients.
Use of antibodies or scFv fragments for diagnostic immunoassays such as ELISA to detect GPC3 protein in samples.
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